Emergence, Retention and Selection: A Trilogy of Origination for Functional De Novo Proteins from Ancestral LncRNAs in Primates

Abstract

While some human-specific protein-coding genes have been proposed to originate from ancestral lncRNAs, the transition process remains poorly understood. Here we identified 64 hominoid-specific de novo genes and report a mechanism for the origination of functional de novo proteins from ancestral lncRNAs with precise splicing structures and specific tissue expression profiles. Whole-genome sequencing of dozens of rhesus macaque animals revealed that these lncRNAs are generally not more selectively constrained than other lncRNA loci. The existence of these newly-originated de novo proteins is also not beyond anticipation under neutral expectation, as they generally have longer theoretical lifespan than their current age, due to their GC-rich sequence property enabling stable ORFs with lower chance of non-sense mutations. Interestingly, although the emergence and retention of these de novo genes are likely driven by neutral forces, population genetics study in 67 human individuals and 82 macaque animals revealed signatures of purifying selection on these genes specifically in human population, indicating a proportion of these newly-originated proteins are already functional in human. We thus propose a mechanism for creation of functional de novo proteins from ancestral lncRNAs during the primate evolution, which may contribute to human-specific genetic novelties by taking advantage of existed genomic contexts.

What Signatures Dominantly Associate with Gene Age?

“…Consistently and strikingly, our results demonstrate that regardless of being duplicates or singletons, GC content is an overwhelmingly dominant signature associating closely with gene age. Conforming to this point, additional evidence has shown by a recent study that de novo new genes originating from long noncoding RNAs present heterogeneity in GC content (Chen et al 2015). …”

Fact or fiction: updates on how protein-coding genes might emerge de novo from previously non-coding DNA

“…Nevertheless, the criteria might be necessary to prevent an over-annotation of spurious transcripts as genes, but they also make it impossible to identify all de novo genes. Recent studies on de novo protein-coding genes also employed such thresholds on exon number and expression strength to produce a more robust data set 15, 17, 18 .…”

“…The first mechanism is transcription-first, where an intergenic sequence gains transcription before evolving an ORF 20, 30 . Recently, this has been shown to happen frequently when long non-coding RNAs (lncRNAs) become protein coding 17, 31, 32 . Consequently, lncRNAs could represent an intermediate step in the evolution of a protein-coding gene 33 .…”

“…measured in the ratio of non-synonymous to synonymous mutations, can be used to infer the coding status of sequences. Genes with a higher fraction of synonymous mutations compared to non-synonymous mutations can be expected to be protein coding and under purifying selection 17, 20 . However, these measures require a number of orthologs to be present, which makes them of limited use for novel genes.…”

“…As it stands, studies mostly have to rely on arbitrary cutoffs 15, 17 and thus might miss a number of genes. It would be of major interest to be able to differentiate de novo genes and protogenes from transcriptional noise.…”